Methods and compositions for inhibiting the growth of aberrant cells are desirable in a variety of situations, for example, to suppress the growth of pathogenic microorganisms infecting a host subject or to suppress the growth of cancer cells in a host subject. Various types of agents for inhibiting aberrant cell growth have been developed. For example, to inhibit the growth of bacterial cells, natural antibiotics (chemical substances produced by microorganisms such as bacteria, fungi and actinomycetes) have been identified and characterized. Synthetic antibiotics, such as sulfonamides and quinolones, have also been developed. Growth of mammalian cells (e.g., malignant cells) can be inhibited by a variety of toxic compounds or therapies, such as nucleoside analogs, metal-containing drugs or radiation treatment, which interfere with normal cellular metabolism.
Transformation, or malignant transformation, of cells results in changes in their growth characteristics and can cause them to form tumors in the infected animals. For example, aberrant cells can be associated with changes in growth control, cell morphology, membrane characteristics, protein secretion and gene expression. Although aberrant cell transformation can occur spontaneously, it can be caused by a chemical or irradiation or may result from infection by a tumor virus. Little is known about the underlying molecular events.
DNA ligase is an enzyme which is involved in DNA replication, repair and recombination. DNA ligase acts by joining single and doubled stranded DNA with the formation of phosphodiesters bonds. For example, eurkaryotic DNA ligases react with ATP, thereby forming covalent enzyme-AMP intermediates. The enzymes then transfer the AMP group to the 5xe2x80x2 end of the DNA to complete the joining reaction. DNA ligase joining activity has been implicated in the proliferation of aberrant cell growth, such as in bacteria and in mammalian cancer.
Although known growth inhibitory agents have been used successfully to suppress the growth of cells to ameliorate certain disease states, there are limitations to their use. For example, the widespread use of antibiotics has increasingly led to the problem of resistant pathogens whose growth can no longer be inhibited by known antibiotics. The appearance of multi-drug resistant pathogens has prompted a search for new classes of antibiotics which are structurally and/or functionally different from existing drugs. Drugs having new mechanisms of action could be effective against resistant microorganisms, where conventional drugs can no longer be used. Chemotherapeutic agents for suppressing the growth of mammalian cells (e.g., malignant cells) also have limitations. Chemotherapeutic agents often have deleterious side effects and/or show only limited efficacy.
The present invention is based, at least in part, on the discovery that certain xcex1-pyrones can be used to treat an xcex1-pyrone responsive state. Examples of such states include undesirable cell proliferation, bacterial infection, or cancer. In a preferred composition and method, the xcex1-pyrone includes a sugar moiety as a solubilizing moiety and an alkyl ester as a cell penetrating moiety.
The present invention provides methods for controlling undesirable cell proliferation in a mammal by administering to the mammal a therapeutically effective amount of an xcex1-pyrone, such that control of undesirable cell proliferation in the mammal occurs.
The present invention also provides methods for controlling a bacterial infection in a mammal by administering to a mammal a therapeutically effective amount of an xcex1-pyrone, such that control of a bacterial infection in the mammal occurs.
The present invention further provides methods for treating cancer in a mammal by administering to the mammal a therapeutically effective amount of an xcex1-pyrone, such that treatment of the cancer in the mammal occurs.
The present invention provides methods for treating diseases characterized by aberrant DNA ligase joining activity in a mammal by administering to the mammal a therapeutically effective amount of an xcex1-pyrone, such that aberrant DNA ligase joining activity in the mammal is treated. The DNA ligase joining activity can be associated with undesirable cell proliferation, such as bacterial or cancer proliferation.
The present invention provides new and useful compounds, xcex1-pyrones, and combinations of such compounds. Subgenuses of xcex1-pyrones that are included in this invention are described below. It should be understood that combinations of xcex1-pyrones within each of these subgenuses are intended to be part of this invention. It should also be understood that such combinations of xcex1-pyrones can be used within the pharmaceutical compositions, packaged pharmaceuticals and methods described herein.
The first subgenus of this invention has the formula 
and pharmaceutically acceptable salts or esters thereof. X is O, S, N or P. R1 or R2 are each independently a hydrogen atom or a cell penetrating moiety and R3 is a solubilizing moiety. Preferably, R1 is a cell penetrating moiety, such as a substituted or unsubstituted alkyl ester group and R3 is a solubilizing moiety, such as a sugar.
The invention also provides new and useful compounds, xcex1-pyrones, having the formula 
and pharmaceutically acceptable salts or esters thereof. X is O, S, N or P. R1 or R2 are each independently a hydrogen atom or a lipophilic solubilizer and R3 is a solubilizing moiety. Preferably, R1 is a lipophilic solubilizer, such as a substituted or unsubstituted alkyl ester group and R3 is a solubilizing moiety, such as a sugar.
The invention further provides new and useful compounds, such as xcex1-pyrones, having the formula: 
and pharmaceutically acceptable salts or esters thereof. X is O, S, N or P. R1 or R2 are each independently a hydrogen atom or a hydrophobic moiety and R3 is a solubilizing moiety. In one embodiment, R1 is a hydrophobic moiety, R2 is a hydrogen atom and R3 is a hydrophilic moiety. In a preferred embodiment, X is O, the hydrophobic moiety is the alkyl ester group 
R5 is a methyl group, R6 is a covalent bond to the xcex1-pyrone ring and the hydrophilic moiety is a sugar moiety.
The invention further provides pharmaceutical compositions for treating an xcex1-pyrone responsive state in a mammal. The pharmaceutical compositions include a therapeutically effective amount of an xcex1-pyrone described supra and a pharmaceutically acceptable carrier.
The present invention also provides packaged pharmaceutical compositions for treating an xcex1-pyrone responsive state in a mammal. The packaged pharmaceutical compositions include a container holding a therapeutically effective amount of at least one xcex1-pyrone, as described supra, and instructions for using the xcex1-pyrone for treating an xcex1-pyrone responsive state in the mammal.
The present invention further provides the new and useful xcex1-pyrones having the formulae 
In one embodiment, the above depicted xcex1-pyrone(s) is isolated from a fungal extract.